The human ether-a-go-go-related gene (HERG) encodes a potassium channel expressed in the ventricular myocardium and is involved in terminating the ventricular action potential. Block of HERG can, in some individuals, result in the lethal arrhythmia Torsade de Pointes, characterized by severely compromised cardiac output. Currently a large number of pharmaceutical compounds still in use have been shown to block HERG. Patients taking these medications are thus at risk for Torsade de Pointes and the clinician must weigh this risk against the benefit of the particular medication. Many patients present with serum electrolyte imbalances due to a large number of common disorders including gastrointestinal dysfunction, renal failure, and a number of endocrine disorders such as hyperparathyroidism. In addition there is an increase in the incidence of electrolyte imbalances with age. Many of these patients often require pharmacological intervention, sometimes with compounds that block HERG, and it is not known if changes in the extracellular environment in individuals within this large patient population will affect a patient's risk for Torsade de Pointes. This project proposes to address this issue by using electrophysiological recordings in Xenopus oocytes expressing either wild type HERG channels or mutant HERG channels to study the mechanisms by which the extracellular monovalent cations potassium, rubidium, and cesium and the divalent cations calcium and magnesium alter block of HERG by a number of different compounds selected based on their different mechanisms of action on the HERG channel. Mutations in HERG at amino acids thought to be involved in drug block combined with mutations in HERG that alter gating will be used to assess the importance of a number of amino acid residues in stabilizing HERG drug interactions as a result of conformational changes during inactivation and deactivation. Certain medications can produce a lethal cardiac side effect. This project will help physicians weigh the risk of this side effect relative to the benefit of the medication, in the aging population, as well as in patients with a number of common disorders, including gastrointestinal and kidney dysfunction. This project will also help develop safer drugs devoid of this lethal side effect. [unreadable] [unreadable] [unreadable]